1. The Field of the Invention
The present invention relates to a noninvasive method for measuring temperature changes in tissues in a subject during and after heating to detect disease or dysfunction of the tissues, to monitor the progress and/or treatment of such disease or dysfunction and to detect the flow of body fluids. In particular embodiments, such measurements may be used to prepare images of the tissues, fluid pathways and related matter.
2. Background of the Invention
Body tissues, including solid tissues such as organs, for example the kidney, liver and spleen, are vulnerable to a number of diseases, such as cancer, inflammation, scarring and deleterious changes in functioning that cause a change in physical characteristics of the tissue. For example, inflammation causes swelling, scarring results in increased density, and alterations in function can create changes in metabolic energy. Such physical changes may also result in changes in the manner in which tissue warms and dissipates applied heat. For example, tissues infiltrated by cancer have been observed to exhibit differential heating characteristics when heat is applied to the tumors (Song, “Blood flow in tumors and normal tissues in hyperthermia,” in Hyperthermia in Cancer Therapy (Storm, ed.), GK Hall Medical Publisher, Boston, Mass., pp 187–206 (1983)).
Currently, imaging of solid tissues to detect the presence and extent of diseases such as cancer is conducted using procedures such as fluoroscopy, ultrasound and x-ray radiation. Nuclear magnetic resonance (NMR) has been used to provide temperature images of solid tissues (U.S. Pat. Nos. 4,558,279 and 4,554,925). Each procedure offers advantages and disadvantages, and often more than one procedure is used to complement the other and assess a patient's condition. The measurement of temperature changes has been used to monitor hyperthermia treatments (U.S. Pat. No. 4,638,436).
The warming of tissue in humans using external energy has been previously described, for example using microwave technology in urology to a limited extent for treatment of tumors in adults. (Hornback, Hyperthermia and Cancer: Human Clinical Trial Experiments Vol. II, CRC Press, Boca Raton, Fla. (1984)). Radio frequency and electromagnetic radiation have been used to treat tumors. (U.S. Pat. No. 3,991,770 and U.S. Pat. No. 4,140,130). Microwave radiometry has been used to measure body temperatures (U.S. Pat. No. 4,583,869) for diagnosis, for example for tumor detection (see Foster and Cheever, Bioelectromagnetics 13:567–579 (1992)).
Various conditions exist in which body fluids, such as urine or blood, improperly flow as a result of disease or dysfunction. For example, vesicoureteral reflux involves movement of urine from the bladder through the ureters to the kidneys contributing to kidney infection, particularly in children. Similarly, gastroesophageal reflux is common in young children and requires nasogastric tubes to be placed to instill x-ray contrast to image whether reflux occurs. Other conditions involve disruptions in blood flow or myocardial function resulting from narrowing of the aorta, blood clots, or malfunction of the enterohepatic circulation or a portion of this system, e.g. the intestine, liver or gall bladder, or disruptions in flow of cerebrospinal fluid. Previously, diagnosis of such conditions has required invasive procedures such as use of catheters or tubes.
In pediatric urology there is a great need to noninvasively measure whether urine from the bladder refluxes to the kidneys. Diagnostic procedures are recommended for all children who have urinary tract infections and for many who suffer from bladder dysfunction causing wetting. Such studies may reveal abnormalities such as urine backflow to the kidney referred to as “reflux.” Reflux is critical to diagnose because in its presence the majority of kidney damage during childhood occurs.
Currently two radiologic imaging studies are utilized: voiding cystourethogram (VCUG) and a nuclear cystogram. A VCUG is performed in humans of all ages by first placing a sterile catheter in the patient's urethra and through the catheter instilling radiopaque contrast, such as Hypaque™, into the bladder under 60 centimeters of gravity pressure. The kidneys and bladder are observed during a bladder filling and emptying cycle using x-rays. The patient has as initial x-ray film taken, then an anterior-posterior film and then films in each lateral oblique. When voiding is initiated, fluoroscopy is utilized, and spot films are taken to document changes during voiding. This process is necessary to evaluate bladder anatomy, function, elimination and vesicoureteral reflux.
An alternative diagnostic study called a nuclear cystogram still requires the ordeal of catheter passage into the urethra and then radioactive particles are instilled into the bladder. Nuclear cystogram is performed after a sterile catheter is placed in the patient's urethra. Radionuclide is instilled into the bladder and the patient is imaged with a gamma camera to evaluate bladder function, elimination and vesicoureteral reflux. The radiation dose is reduced but not eliminated. Moreover, visual images obtained from this study are typically of poor quality.
Although it is the bladder that is invaded by a catheter in these diagnostic procedures, the critical information obtained involves the kidneys and leads to protection from kidney damage. If reflux of urine to the kidney is detected, the diagnostic tests need to be repeated in the same child at regular intervals until the reflux is resolved. Repeat tests heighten the anxiety of the child and the parents.
These examinations have been utilized for years and are very familiar to pediatricians and adult physicians alike. A limitation of VCUG's or nuclear cystograms is availability. These studies are currently performed in hospital radiology departments and generally are not available on a same day basis. It would be advantageous for physicians to be able to carry out a noninvasive procedure to detect organ or tissue dysfunction at the point of care clinic or office.
The majority of the patients undergoing these studies are children and the placement of urethral catheters is an ordeal for the patients and the medical personnel. In addition, VCUG carries risks of urethral damage and urinary tract infection. The need exists for a noninvasive, catheterless, technique for evaluating bladder function—e.g. process of bladder emptying, elimination and vesicoureteral reflux. This is very important in adults with outlet obstruction who empty their bladders poorly. This currently is measured with a postvoid catheter or with ultrasound.
Currently the degree of vesicoureteral reflux is graded on an international scale of 1 to 5. Treatment is based upon the grade given to the reflux to each kidney and either medical management or surgical treatment is chosen. Generally Grades 1 thru 3 are assigned nonsurgical management while Grades 4 and 5 are surgically corrected.
In children, categories of patients who currently undergo VCUG's or nuclear cystograms are: 1) newborns with antenatal hydronephrosis (water-swollen kidneys); 2) patients during childhood who have a urinary tract infection; and 3) patients with enuresis (urinary incontinence) either during the day or night. One out of every 200 babies have antenatal hydronephrosis discovered prior to delivery. Most of these patients will have this kidney dilation confirmed postnatally and require a VCUG along with a renal ultrasound. In male children it may be necessary to continue to perform VCUG's to better visualize the anatomy of the urethra, but in female children and some of the males, a noninvasive study would be indicated.
Approximately 2% of all children at any one time have a urinary tract infection. After the first infection it is currently recommended that patients undergo a VCUG and a renal imaging study. Doctors are sometimes reluctant to order the invasive VCUG until other infections occur. Of the VCUGs performed, approximately one of three patients will have vesicoureteral reflux. The reflux is graded and treatment is assigned on the basis of severity. About three-quarters of the patients are assigned to medical management and are screened with a VCUG each year until their reflux resolves. This averages about three years of waiting before resolution occurs. Patients who undergo surgical correction of their reflux also require a follow-up VCUG to evaluate the success of the procedure. Patients with enuresis either at night or during the day are evaluated with VCUGs on occasion. Since the test is currently invasive it is withheld until the patients are older or unusual symptoms indicate its necessity.
To synthesize these numbers in Group 1, every patient would need a VCUG. In Group 2, all children should have a VCUG and one out of every three would need a VCUG. Group 3 would still have a significant number of studies and if noninvasive technology was available even more studies would be performed. While adults undergo VCUG's less frequently, the procedure is still uncomfortable and simple, relatively inexpensive, noninvasive studies would still be desirable.
The warming of tissue in humans using external energy has been previously described, for example using microwave technology in urology to a limited extent for treatment of tumors in adults. (Hornback, Hyperthermia and Cancer: Human Clinical Trial Experiments, Vol. II, CRC Press, Boca Raton, Fla. (1984)). Radio frequency and electromagnetic radiation have been used to treat tumors. (U.S. Pat. No. 3,991,770 and U.S. Pat. No. 4,140,130). Microwave radiometry has been used to measure body temperatures (U.S. Pat. No. 4,583,869) for diagnosis, for example for tumor detection (see Foster and Cheever, Bioelectromagnetics 13:567–579 (1992)).
Diagnostic uses of microwave radiometry have also been proposed for a variety of conditions including measurement of blood flow rates in tissues, such as flow of cerebral blood (Gabrielyan et al., in Methods, pp 713–715, Plenum Press, NY (1987)) and changes in lung water content (Iskander et al., IEEE Trans Microwave Theory Tech MTT 32:554–556 (1984); U.S. Pat. No. 4,488,559). Gabrielyan et al. heated a part of the brain using microwaves and measured the rate of temperature drop of the tissue using a radiometer to determine the rate of cerebral blood flow. Iskander et al. used radiometry to detect changes in lung water content by measuring emitted microwave radiation.
In these prior known methods externally applied energy was not used to heat tissues, to measure warming or heat dissipation characteristics, for the purpose of detecting and/or monitoring the condition of the tissues within a subject, or to construct images of the tissue from such measurements for diagnostic purposes. Furthermore, externally applied heat was not employed to warm fluid within tissue or organs, in order to follow its flow path and determine the presence of disease or dysfunction within a subject. Thus, there remains a need for noninvasive methods to evaluate the condition of tissues, to determine or monitor the presence of disease and/or dysfunction.
A need also remains for noninvasive methods to track the flow of body fluids, such as urine, from one location within a subject to another, to determine the presence of disease and/or dysfunction and to monitor the progress of the disease and/or medical intervention.